RESUMEN
Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.
Asunto(s)
Enfisema , Hiperhomocisteinemia , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Animales , Apoptosis , Modelos Animales de Enfermedad , Enfisema/etiología , Homocisteína , Humanos , Hiperhomocisteinemia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfisema Pulmonar/etiología , Enfisema Pulmonar/metabolismo , Nicotiana/efectos adversosRESUMEN
BACKGROUND: Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD. METHODS: A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated. RESULTS: A total of 33 studies were included in this meta-analysis. LAMA significantly decreased the frequency of exacerbations compared to the placebo (OR 0.75; 95% CI 0.66 to 0.85; P < 0.001). The mean changes in the St George's Respiratory Questionnaire score (mean difference, -3.61; 95% CI, -4.27 to -2.95; P < 0.00001), transitional dyspnea index score (mean difference 1.00; 95% CI 0.83 to 1.17; P < 0.00001), and trough FEV1 (mean difference 0.12; 95% CI 0.11 to 0.13; P < 0.0001) indicated significantly greater improvement in the LAMA group than the placebo group. The number of withdrawals due to adverse events in the LAMA group was significantly fewer than that in the placebo group (OR -0.02; 95% CI -0.03 to -0.01; P = 0.002). CONCLUSION: LAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV1, QoL, and dyspnea score for stable COPD.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Broncodilatadores/uso terapéutico , Humanos , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Bromuro de Tiotropio/uso terapéutico , Resultado del TratamientoRESUMEN
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.
Asunto(s)
Enfisema/etiología , Deficiencias de Hierro , Fumar/efectos adversos , Células A549 , Animales , Líquido del Lavado Bronquioalveolar , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfisema/sangre , Recuento de Eritrocitos , Humanos , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Iones , Hierro/sangre , Quelantes del Hierro/farmacología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
BACKGROUND: Oxidative stress is a major cause of cardiovascular disease. Superoxide dismutase-1 (SOD1) is an antioxidant that protects against oxidative stress. Deoxyribonucleic acid (DNA) variations such as single nucleotide polymorphism (SNP) or haplotypes within the SOD gene are reportedly associated with the development of cardiovascular disease. However, it remains to be determined whether SOD1 variability is associated with cardiovascular or all-cause mortality in the general population. METHODS AND RESULTS: This prospective cohort study included 2799 subjects who participated in a community-based health study with a 10-year follow-up. We genotyped 639 SNPs and found the association of SNP rs1041740 and rs17880487 within a SOD1 gene with cardiovascular mortality. There were 193 deaths during the follow-up period including 57 cardiovascular deaths. Multivariate Cox proportional hazard regression analysis revealed that the homozygous T-allele of rs1041740 was associated with all-cause and cardiovascular deaths after adjusting for confounding factors. The net reclassification index was significantly improved by adding rs1041740 as a cardiovascular risk factor. On the other hand, cardiovascular death was not observed in homozygous T-allele carriers of rs17880487. Haplotype analysis identified the haplotype with T-allele of rs1041740 and that with T-allele of rs17880487 as increasing and decreasing susceptibility for cardiovascular mortality, and it had complementary SNP sequences. CONCLUSION: Variation in the SOD1 gene was associated with cardiovascular deaths in the general population.
Asunto(s)
Enfermedades Cardiovasculares/genética , Variación Genética , Superóxido Dismutasa-1/genética , Anciano , Alelos , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/patología , Causas de Muerte , Estudios de Cohortes , Femenino , Genotipo , Haplotipos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de RiesgoRESUMEN
In the treatment of chronic obstructive pulmonary disease (COPD), bronchodilators such as long acting muscarinic antagonist (LAMA) and long acting ß agonist(LABA) play key roles for improving respiratory function and symptoms, and reducing risk of exacerbation. However, inhaled corticosteroid (ICS), a key medicine for bronchial asthma, is limitedly used in COPD treatment. Japanese Respiratory Society recommends to use ICS for severe COPD patients who have been frequently exacerbated, because previous clinical studies indicated that ICS reduces exacerbation in moderate to severe COPD patients. Asthma sometimes overlaps with COPD, and symptoms of those patients are not well controlled by the bronchodilation therapy alone. Therefore, ICS/LABA or ICS/LAMA should be prescribed to those overlapped patients. Concentration of exhaled nitrogen oxide and percentage of peripheral eosinophil may be good biomarkers for discriminating the COPD patients who have good response to ICS treatment.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncodilatadores/administración & dosificación , Glucocorticoides/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Asma/complicaciones , Asma/tratamiento farmacológico , Asma/fisiopatología , Biomarcadores/análisis , Pruebas Respiratorias , Combinación Budesonida y Fumarato de Formoterol/administración & dosificación , Preparaciones de Acción Retardada , Progresión de la Enfermedad , Combinación de Medicamentos , Quimioterapia Combinada , Eosinófilos , Fluticasona/administración & dosificación , Humanos , Recuento de Leucocitos , Óxidos de Nitrógeno/análisis , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Xinafoato de Salmeterol/administración & dosificación , Índice de Severidad de la Enfermedad , Bromuro de Tiotropio/administración & dosificaciónRESUMEN
BACKGROUND: Serum heart-type fatty acid-binding protein (H-FABP) has been widely used as a marker of cardiac myocyte injury. This study was carried out to examine the relationships of H-FABP levels with age, gender, and other physiologic characteristics in a large population of community-dwelling residents. METHODS AND RESULTS: Serum H-FABP levels were measured in 2,099 subjects who received an annual health check-up (age 40-87 years). The relationships between H-FABP and blood pressure, laboratory data, electrocardiogram (ECG) findings, and lifestyle factors were cross-sectionally analyzed. Mean H-FABP values were significantly higher in men than in women. Serum H-FABP levels were increased with aging significantly. Both the multivariate regression and multiple logistic regression analyses indicated that serum H-FABP levels were independently affected by age, body mass index, creatinine clearance, and ECG abnormality score. CONCLUSION: Serum H-FABP levels were affected by age, gender, obesity, renal function, and ECG abnormality in a large group of volunteers. These effects should be taken into account in determining appropriate reference values for H-FABP. In addition, high serum H-FABP levels may represent latent cardiac injury and have important clinical implications.